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CN102421748B - Method for obtaining optically pure amino acids - Google Patents

Method for obtaining optically pure amino acids Download PDF

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Publication number
CN102421748B
CN102421748B CN201080020567.5A CN201080020567A CN102421748B CN 102421748 B CN102421748 B CN 102421748B CN 201080020567 A CN201080020567 A CN 201080020567A CN 102421748 B CN102421748 B CN 102421748B
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amino acid
aqueous solution
solution
organic
group
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CN102421748A (en
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金宽默
金浩准
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AMINOLUX Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/02—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of urea, its salts, complexes or addition compounds
    • C07C273/14—Separation; Purification; Stabilisation; Use of additives
    • C07C273/16—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/36—Racemisation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/189—Purification, separation, stabilisation, use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a method for obtaining optically pure amino acids, including optical resolution and optical conversion. The method of the present invention significantly shortens the time taken for optical transformation, and enables the repeated use of an organic solution containing a chiral selective receptor, to thereby obtain optically pure amino acids in a simple and remarkably efficient manner, and to enable the very economical mass production of optically pure amino acids.

Description

Process for preparing optically pure amino acids
Technical Field
The present invention relates to a method for preparing optically pure amino acids by an extraction process comprising optical resolution and optical conversion (optical conversion).
Background
Optically pure amino acids are used as ligands for asymmetric catalysts (asymmetric catalysts) or can be widely used as raw materials or intermediates required for the synthesis of various medical products and physiologically active substances, and thus are very important compounds from an industrial point of view (Helmchen, G.; Pfaltz, A.Acc.chem.Res.2000, 33, 336-.
Amino acids can be produced inexpensively and economically by fermentation. However, the amino acids produced by fermentation are limited to only L-amino acids among natural amino acids. Although optically pure D-amino acids and unnatural amino acids are produced by an enzymatic treatment or an optical resolution method, their production cost is large, and therefore their price is 5 to 10 times higher than that of natural L-amino acids produced by fermentation, and it is difficult to realize mass production (Maruoka, k.; oii, t.chem.rev.2003, 103, 3013.).
The present inventors developed a method for converting an L-amino acid into a D-amino acid by forming an imine bond ((a) Park, H.; Kim, K.M.; Lee, A.; Ham, S.; Nam, W.; Chin, J.J.Am.Chem.Soc.2007, 129, 1518-.
[ binaphthol derivative ]
The binaphthol derivatives can react chirally selectively with amino acids to form imines and enable L-D optical conversion of amino acids in organic solvents (e.g., DMSO). The L-D optical transformation method is optical transformation in DMSO followed by extraction of the whole solution with water and organic solvents as disclosed in previous patents and papers (Park, H.; Kim, K.M.; Lee, A.; Ham, S.; Nam, W.; Chin, J.J.Am.chem.Soc.2007, 129, 1518-. By this method, the amino acid is transferred into the aqueous layer and the binaphthol derivative is transferred into the organic layer, and the binaphthol derivative in the organic layer can be recovered by concentration for recycling. When the method is used for carrying out the L-D optical conversion, the time required for carrying out the optical conversion is about 24-48 hours. Since DMSO solvent is readily soluble in water and organic solvents, recovery of DMSO is not possible. Further, in order to recover the binaphthol derivative, it is necessary to completely remove DMSO in the organic layer. For this reason, a large amount of water must be used, which increases the working volume and decreases the productivity. In addition, when another water-insoluble solvent is used instead of DMSO, there is a problem in that the L-D optical conversion reaction time is further prolonged.
Disclosure of Invention
Technical problem
The present invention has been made to solve the above-mentioned problems occurring in the prior art, and an object of the present invention is to provide a method for preparing an optically pure amino acid, which can greatly shorten the reaction time for optical conversion, enables the reuse of an organic solution containing a chirally selective acceptor, and does not require the concentration of an organic solvent used, thereby enabling the production of an optically pure amino acid very economically and efficiently.
Technical scheme
The present invention provides a method for preparing an optically pure amino acid, which method uses: an aqueous alkaline solution comprising an amino acid for optical resolution or optical conversion; an organic solution comprising a chirally selective receptor that undergoes a chirally selective reaction with a D-amino acid or an L-amino acid to form an imine; and an acidic aqueous solution; the method comprises the following steps: a first step of mixing the alkaline aqueous solution and the organic solution by stirring and separating an alkaline aqueous solution layer and an organic solution layer; a second step of mixing the organic solution and the acidic aqueous solution separated in the first step by stirring and separating an acidic aqueous solution layer and an organic solution layer; and a third step of obtaining a D-amino acid or an L-amino acid from the acidic aqueous solution separated in the second step.
The method may further comprise: repeating the first step and the second step one or more times using the basic aqueous solution separated in the first step and the acidic aqueous solution and the organic solution separated in the second step before performing the third step.
In the method, the amino acid contained in the basic aqueous solution is in the form of a lithium salt, a sodium salt, or a potassium salt of the amino acid.
In the method, the basic aqueous solution may further comprise a racemization catalyst to effect racemization of the amino acid. Meanwhile, in order to accelerate the racemization, the basic aqueous solution containing the racemization catalyst may be heated to 50 ℃ to 100 ℃ and then the first step may be performed.
In the method, the organic solvent contained in the organic solution is a mixed solvent containing a water-insoluble organic solvent and an organic solvent having a high-polarity functional group.
In the method, the organic solution further comprises a Phase Transfer Catalyst (PTC).
In the method, the amino acid is an alpha-amino acid or a beta-amino acid.
The present invention also provides a process for accelerating the racemization of an amino acid which comprises adding a racemization catalyst to an aqueous basic solution containing an amino acid and heating the aqueous solution to 50 ℃ to 100 ℃.
Advantageous effects
The method of the present invention can greatly shorten the reaction time of optical conversion and can reuse the organic solution containing the chiral selective receptor without concentrating the used organic solvent. Therefore, an optically pure amino acid can be obtained by a simple method and can be produced economically on a large scale.
Drawings
FIG. 1 is a schematic diagram of an implementation of the method of the invention;
FIG. 2 is1H NMR spectrum showed chiral selectivity of imine formed by bonding amino acid and chiral selective acceptor in example 5 of the present invention.
Detailed Description
The invention relates to a method for producing optically pure amino acids, using: an aqueous alkaline solution comprising an amino acid for optical resolution or optical conversion; an organic solution comprising a chirally selective receptor that undergoes a chirally selective reaction with a D-amino acid or an L-amino acid to form an imine; and an acidic aqueous solution. The method comprises the following steps: a first step of mixing the alkaline aqueous solution and the organic solution by stirring and separating an alkaline aqueous solution layer and an organic solution layer; a second step of mixing the organic solution and the acidic aqueous solution separated in the first step by stirring and separating an acidic aqueous solution layer and an organic solution layer; and a third step of obtaining a D-amino acid or an L-amino acid from the acidic aqueous solution separated in the second step.
Before performing the third step, the method may further include: repeating the first step and the second step one or more times using the basic aqueous solution separated in the first step and the acidic aqueous solution and the organic solution separated in the second step.
In the method of the present invention, the term "optical resolution" means resolution of a mixed D-amino acid and L-amino acid into a D-amino acid and an L-amino acid; the term "optical conversion" means the conversion of an L-amino acid into a D-amino acid or the conversion of a D-amino acid into an L-amino acid, thereby obtaining an optically pure amino acid.
To aid in the understanding of the present invention, FIG. 1 illustratively depicts the method of making an optically pure amino acid. As shown in FIG. 1, while the organic solution shuttles between the basic aqueous solution and the acidic aqueous solution, the organic solution selectively transfers the D-amino acid among racemic amino acids (DL-amino acids) in the basic aqueous solution to the acidic aqueous solution. In this case, when racemization occurs in an aqueous basic solution, all the amino acids in the aqueous basic solution are converted into D-amino acids, which are then transferred into an aqueous acidic solution. In the case where racemization does not occur in an aqueous basic solution, only the D-amino acid in the aqueous basic solution is transferred to an aqueous acidic solution, whereby resolution of the L-amino acid and the D-amino acid occurs.
The method of the present invention will be described in detail below for each constituent element.
1. Alkaline aqueous solution
In the present invention, the basic aqueous solution provides an amino acid for optical resolution and optical conversion, and is prepared to be basic so that the chirally selective acceptor in the organic solution efficiently reacts with the amino acid to form an imine bond. Generally, the basic aqueous solution may be prepared by dissolving a lithium salt, sodium salt or potassium salt of an amino acid into distilled water. The lithium salt, sodium salt or potassium salt of the amino acid can be prepared by adding NaOH, KOH, or the like to the amino acid. In this case, the molar amount of NaOH or KOH may be the same as, slightly greater than, or less than the molar amount of amino acids. The molar amount may be optimized according to the stability of the amino acid, the degree of racemization, chiral selectivity, etc. In addition, the basic aqueous solution may further comprise a racemization catalyst for racemizing the amino acid.
In the present invention, it is preferable to use a racemization catalyst which is soluble in water but insoluble in an organic solvent.
The racemization catalyst may include a salicylaldehyde derivative. Such salicylaldehyde derivatives have a hydroxyl group (-OH) and an aldehyde group (-CHO), and are adjacent to each other, and thus can form a stable imine bond (-CH ═ N-) with an amino acid, thereby inducing racemization of the amino acid. Examples of the salicylaldehyde derivative may include PLP (pyridoxal-5' -phosphate, pyridoxal-5-phosphate), pyridoxal (pyridoxal), and the like, which may be used alone or in combination of two or more. In particular, PLP can be preferably used as a racemization catalyst.
The racemization catalyst is most suitably used in an amount of 5% by mole of the amino acid, but may vary depending on the type of the amino acid.
2. Organic solvent
In the present invention, the organic solution comprises a chirally selective acceptor dissolved therein. The chiral selective receptor refers to a compound which reacts chirally selectively with amino acids and forms imines. For example, where the chirally selective acceptor is S-type, it is chirally selective for D-amino acids. However, where the chirally selective acceptor is of the R-type, it is chirally selective for L-amino acids. However, such chiral choices may vary depending on the type of compound.
For example, in the present invention, when the S-chirally selective acceptor is dissolved in the organic solution layer, D-amino acid among racemic amino acids in the basic aqueous solution layer selectively reacts with the S-chirally selective acceptor to form imine, thereby transferring into the organic solution layer.
In the present invention, the chiral selective receptor can be used without limitation as long as the chiral selective receptor can chirally selectively react with an amino acid to form an imine, so that the amino acid can be transferred from an aqueous solution layer to an organic solution layer. In particular, any derivative having a salicylaldehyde group that can form an imine with an amino acid can be used in the method of the present invention, as long as it has chiral selectivity. Even if the provided compound does not have a salicylaldehyde group, it can be used without limitation in the present invention as long as the compound has chiral selectivity for amino acids and satisfies the conditions as described above.
Preferably, a chiral selective acceptor is used which is insoluble in water but soluble in organic solvents.
The chirally selective receptor useful in the present invention includes, for example, compounds represented by the following chemical formula 1 and chemical formula 2.
[ chemical formula 1]
[ chemical formula 2]
In chemical formulas 1 and 2, X is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, formyl, carboxyl, C1-C10 alkyl, C1-C10 alkylcarbonyl, C6-C10 aryl, and C1-C10 alkoxy, wherein the C1-C10 alkyl is substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, and C6-C10 aryl;
y is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, formyl, carboxyl, C1-C10 alkyl, C1-C10 alkylcarbonyl, C6-C10 aryl and C1-C10 alkoxy, wherein the C1-C10 alkyl is substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro and C6-C10 aryl;
z is independently selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, formyl, carboxyl, C1-C10 alkyl, C1-C10 alkylcarbonyl, C6-C10 aryl and C1-C10 alkoxy, wherein the C1-C10 alkyl is substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro and C6-C10 aryl;
l is an integer of 0 to 5, M is an integer of 0 to 5, and N is an integer of 0 to 3;
r1 is: hydrogen; tosyl (tosyl); CH (CH)3SO2-；CH3CO-; a C1-C10 alkyl group substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; C4-C10 cycloalkyl substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; C4-C10 cycloalkenyl substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; c4 to C10 cycloalkynyl, substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; or a C6-C12 aryl group substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, hydroxy and C1-C5 alkyl;
r2 is-NHCX' R3, -NHS (═ O)aR3、Or-NHC (NHR5)+R4; wherein X' is oxygen or sulfur; a is 1 or 2; r3 and R4 are each independently hydrogen, C1-C10 alkyl which is substituted OR unsubstituted by halogen, -NR6R7 OR OR 8; r5 to R8 are each independently hydrogen, C1-C10 alkyl substituted or unsubstituted with halogen, or C6-C12 aryl, wherein C6-C12 aryl is substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, nitro, C1-C5 alkyl, C1-C5 alkoxy, and C1-C5 perfluoroalkyl; and R5 and R6 may be bonded to form a ring, wherein when R2 is-NHC (NH)2)NH2 +or-NHCHNH2 +When the counter ion (counter ion) is a halide ion or R9COO-R9 is a C6-C12 aryl group substituted or unsubstituted by a C1-C10 alkyl group or a C1-C5 alkyl group;
r10 is: hydrogen; a C1-C10 alkyl group substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; C4-C10 cycloalkyl substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; C4-C10 cycloalkenyl substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; c4 to C10 cycloalkynyl, substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; or a C6-C12 aryl group, substituted or unsubstituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-C5 alkyl, and C1-C5 alkoxy; wherein alkyl refers to linear or branched alkyl.
In the compound of chemical formula 2, the carbon atom bonded to R10 may be R-type or S-type.
Specific examples of the compounds represented by chemical formulas 1 and 2 are shown below.
Compound 3, compound 4 and compound 5 all contain binaphthol-3-formyl-2-hydroxy, and compound 6 is a derivative of a salicyl compound. Compound 3, compound 4, compound 5 and compound 6 can be prepared according to the methods disclosed in published articles and patents ((a) Nandhakumar, r.; Ryu, j.; Park, h.; Tang, l.; Choi, s.; Kim, k.m. tetrahedron 2008, 64, 7704.; B) Kim, k.m., Nam, w.; Park, h.; chi, j.us patent 7,268,252B 2; (c) Kim, k.m. Tang, l.us 2009/0023931 a 1). In addition to the above compounds, other compounds disclosed in the above papers and patents may also be used in the present invention.
In addition, PTC may be added to the organic solution so that the amino acid in the alkaline aqueous solution can be easily transferred to the organic solution layer.
Examples of the PTC include quaternary ammonium salts (quaternary ammonium salt), phosphonium salts (phosphonium salt), and the like, which are widely used. Particularly preferred in the present invention is Aliquat 336(Tricaprylylmethylammonium chloride) as the PTC water-insoluble solution layer. Preferably, the molar amount of PTC added corresponds to the molar amount of the chirally selective acceptor, but the molar amount of PTC may be adjusted to be slightly more or less than the chirally selective acceptor in view of the chiral selectivity and the reaction time required for the formation of the imine.
Organic solvents useful in preparing organic solutions include solvents that are insoluble in water. Such solvents include chloroform, dichloromethane (MC), Ethyl Acetate (EA), toluene, 2-pentanone (2-pentanone), butyronitrile (butyronitrile), tolunitrile (tolulenitrile), methyl isobutyl ketone (methylisobutylketone), or a mixture thereof. In order to increase the chiral selectivity, it is preferable to use a mixture comprising an organic solvent having a high polar group such as nitrile (nitrile), carbonyl (carbonyl), sulfoxide (sulfoxide), etc., and an organic solvent insoluble in water. When an organic solvent having a highly polar group (e.g., nitrile group, carbonyl group, sulfoxide group, etc.) is used alone, chiral selectivity may be improved, but the solvent may be partially soluble in water. Therefore, when the solvent is used together with a water-insoluble solvent, the mixture can be prevented from being miscible with water while improving selectivity. The organic solvent insoluble in water and the organic solvent with high-polarity functional groups can be mixed according to the volume ratio of 1: 9-9: 1.
Examples of the mixed solvent include a mixture of dichloromethane and butyronitrile, a mixture of chloroform and tolunitrile, and the like.
3. Acidic aqueous solution
The acidic aqueous solution is prepared to remove amino acids from imines formed by the reaction of the amino acids with chiral selective receptors in an organic solvent. The acidic aqueous solution can be prepared by different acids. For example, it can be obtained by adding hydrochloric acid (HCl). The appropriate concentration of the acidic aqueous solution depends on the type of amino acid, the reaction time required for hydrolyzing the imine bond, and the like.
4. Principle of the method of the invention
The organic solution and the basic aqueous solution of amino acid are immiscible with each other. When the two layers are stirred by a common method, only one amino acid (D-form or L-form) which can form a bond with a chiral selective receptor (S-form or R-form) in an organic solvent in an aqueous alkaline solution reacts selectively with the chiral selective receptor to form an imine. For example, where the chirally selective acceptor is S-type, the chirally selective acceptor reacts selectively with the D-amino acid to form an imine. After such a chiral selective imine has been formed, the organic solution layer is separated and then stirred with an acidic aqueous solution of dissolved amino acids. At this time, since the acidic aqueous solution is acidic, the amino acid is transferred to the aqueous solution layer while the imine of the organic solution layer is cleaved. The original chiral selective acceptor remains in the organic solution layer and the organic solution can be used unaltered, so that the above process can be repeated. In this case, in the case of continuous racemization of the amino acid in an aqueous basic solution, eventually all the DL-amino acid is converted into the D-amino acid, which is then transferred into an aqueous acidic solution. Alternatively, even when an L-amino acid is added to an aqueous alkaline solution in place of a DL-amino acid, the L-amino acid is immediately racemized, and thus the result is the same as that when a DL-amino acid is added. In the method of the present invention, it takes 2 to 3 hours for the chiral selective transfer of the amino acid from the basic aqueous solution layer to the organic solution layer, and racemization of the amino acid in the basic aqueous solution using an appropriate catalyst can be completed in a short time, so that the L-D optical conversion of the amino acid as a whole can be completed in a short time. According to the method in the known patent, when the optical transformation is carried out in DMSO, a total time of at least several days is required including the reaction and recovery processes. Thus, the process of the present invention is very outstanding in comparison therewith. Further, in the present invention, the organic solution layer containing the chiral selective receptor can be directly reused without additional purification, and thus is very economical.
5. Racemization of amino acids in basic aqueous solutions
A racemization catalyst (e.g., PLP) may be added to the basic aqueous solution providing the amino acid to promote racemization of the amino acid. In aqueous alkaline solutions, PLP forms imines with amino acids, racemizing the amino acids. The amount of PLP is preferably 5% (molar) of the amino acid, but may vary depending on the type of amino acid. At 5 mol% PLP, the racemization of the amino acid proceeds slowly at room temperature and can reach about 30% in a week. The process can be carried out by adding, for example, the sodium salt of phenylalanine and dissolving in heavy water (D)2O) and then observing the degree of deuteration (deuteration) of α -H. Here, the degree of deuteration of α -H shows racemization of amino acid. Even when the amount of PLP reached 20% (by mol), the rate of racemization of the amino acid was not increased any more. However, in the present invention, racemization of amino acid can occur within a short time of 1 hour when the temperature of the aqueous solution is increased to 50 ℃ to 100 ℃. Thus, in order to perform rapid racemization in a basic aqueous solution which provides an amino acid, a baseThe temperature of the aqueous sexual solution can be preferably increased to the above range. When the basic aqueous solution is heated to a temperature below 50 ℃, the accelerating effect of racemization is negligible and the temperature of the aqueous solution cannot be heated above 100 ℃. When the amino acid in the basic aqueous solution layer is transferred to the organic solution layer, the addition of the amino acid to the basic aqueous solution is continued so that the optical conversion can be continued.
6. Principle of chiral selection, principle of chiral transformation and application scope of the invention
The chiral selection of the present invention is based on the structural stability of the imine, the detailed principles of which are disclosed in a number of papers that have been published. In a published paper (JACS 2007; che. eur.j 2008; Tetrahedron 2008), a method for achieving chiral conversion of amino acids in DMSO solvents by using binaphthol or other derivatives is described. Generally, chiral conversion of amino acids does not readily occur in the organic solvents used in the process of the present invention. However, the process provided by the present invention makes possible chiral conversions of all DL-amino acids. This is because the racemization of an amino acid is carried out in an aqueous basic solution. Specifically, by combining racemization in a basic aqueous solution and chirally selectively transferring the amino acid in the basic aqueous solution layer into the organic solution layer, it becomes possible to chirally convert all DL-amino acids. This can be said to be a quite significant result compared to the typical optical resolution with a maximum yield of only 50%.
In the process of the invention, the manual conversion can in principle be used for any alpha-amino acid which can be racemized in aqueous solution. And the method of the present invention can be effectively used for chiral separation of beta-amino acids. By the same principle, the process of the invention can be used for all amines which can form imines with chirally selective acceptors.
Furthermore, the present invention relates to a method for accelerating the racemization of an amino acid, which comprises adding a racemization catalyst to a basic aqueous solution containing an amino acid and heating the aqueous solution to 50 ℃ to 100 ℃.
As described above, in the racemization of an amino acid, even if the amount of the racemization catalyst is increased to 20%, the racemization rate of the amino acid is not increased any more. However, in the present invention, when a racemization catalyst is added and the temperature of the aqueous solution is increased to 50 to 100 ℃, racemization of the amino acid can be completed in a short time of 1 hour. Therefore, in order to carry out rapid racemization in an aqueous solution which provides an amino acid, it is preferable to heat the aqueous solution to the above-mentioned temperature range.
The racemization catalyst may use salicylaldehyde derivatives. The salicylaldehyde derivative has a hydroxyl group (-OH) and an aldehyde group (-CHO), which are adjacent to each other, and thus can form a stable imine bond (-CH ═ N-) with an amino acid, thereby inducing racemization of the amino acid. The salicylaldehyde derivative may contain PLP (pyridoxal phosphate), pyridoxal, and the like, which may be used alone or in combination of two or more. Particular preference is given to using PLP as the racemization catalyst.
The pH of the alkaline aqueous solution is 14 or less but more than 7, preferably in the range of 10 to 12.
Modes for carrying out the invention
Hereinafter, the present invention will be described in more detail by way of examples. However, the following examples are only for illustrating the present invention more specifically, and are not to be construed as limiting the scope of the present invention. And those skilled in the art may suitably modify or change it.
Example 1: preparation of chirally selective receptors
[ Compound 3]
Compound 3 was synthesized according to the synthesis method of compound 1 disclosed in the published paper (Park, h.; Nandhakumar, r.; Hong, j.; Ham, s.; chi, j.kim, k.m.chem.eur.j.2008, 14, 9935). When Compound 3 was synthesized, 4-methylphenylisocyante (4-methylphenylisocyante) was used in place of the phenylisocyanate (phenylisocyanate) used in the above-mentioned paper for the synthesis of Compound 1.
Compound 3:1h NMR (nuclear magnetic resonance) (CDCl3, 250 MHz): δ (ppm) ═ 10.5(s, 1H), 10.2(s, 1H), 8.3(s, 1H), 6.5-8.1(m, 20H), 5.1(dd, 2H), 2.3(s, 3H).
Example 2: preparation of organic solutions
Compound 3(10.0g, 18mmol, S-optical isomer) as a chirally selective acceptor and Aliquat 336(10.0g, 18mmol) as PTC were dissolved in CDCl mixed at 1: 13(50ml) and p-tolunitrile (toluene-4-nitrile, 50ml), to prepare an organic solution.
Example 3: preparation of aqueous alkaline solutions
Phenylalanine (racemate, 30g, 180mmol) and 1.0 equivalent of NaOH were sequentially added to water (100ml) to be completely dissolved, and then 1.5g of PLP was added thereto, thereby preparing an aqueous alkaline solution.
Example 4: preparation of acidic aqueous solutions
Concentrated hydrochloric acid (10g) was diluted 10-fold to prepare 100ml of an acidic aqueous solution.
Example 5: optically selective transfer of phenylalanine
The organic solution and the aqueous alkaline solution prepared above were added to a 2L round bottom flask, followed by stirring for 2 hours and 30 minutes. Taking part of the organic solution layer, and using1H NMR checked whether or not imine was formed (FIG. 2). The results show that compound 3 is all used to form an imine chirally selectively with an amino acid. The chiral selectivity was determined by integration of the ureido-NH signal of Compound 3. The results show a chiral selectivity of approximately 1: 12 at L: D. In FIG. 2, the small peak denoted by L is NH of imine formed by L-phenylalanine, and the peak denoted by D is D-phenylalanineNH of acid formed imine.
The chiral selectivity is the same as that of optical conversion from L-phenylalanine to D-phenylalanine in DMSO (Park, H.; Kim, K.M.; Lee, A.; Ham, S.; Nam, W.; Chin, J.J.Am.chem.Soc.2007, 129, 1518-. The organic solution layer was separated from the aqueous solution layer using a separatory funnel (separation funnel), and then the organic solution layer was stirred with the acidic aqueous solution for 1 hour. After that time, the user can use the device,1the results of H NMR examination showed that all amino acids were separated from compound 3, and that compound 3 and Aliquat 336 were present in the same state in the organic solution layer as before the optical conversion. In addition, the acidic aqueous solution layer has D-phenylalanine separated from the organic solution layer and transferred thereto.
The same process as described above was repeated twice using the alkaline aqueous solution, the organic solution and the acidic aqueous solution that had undergone the above-described optical selective transfer once. For each repetition of the experiment, 2.97g (18mmol) of racemic phenylalanine and the same molar amount of NaOH were added to the aqueous alkaline solution so as to maintain the predetermined molar amount of phenylalanine in the aqueous alkaline solution. In the second and third replicates, the chiral selectivity was slightly less than in the first. This is considered to be due to the occurrence of the optically selective transfer, so that the proportion of L-phenylalanine in the aqueous alkaline solution is slightly increased.
The L-form ratio of phenylalanine in the basic aqueous solution was increased, so that the aqueous solution layer was heated and stirred at 90 ℃ for 1 hour so that racemization occurred, and then the experiment was repeated as described above. The chiral selectivity of phenylalanine is the same as the first experimental result, the phenylalanine is transferred from the basic aqueous solution in which the racemization occurs to the organic solution.
Thereafter, the experiment was repeated in the same manner as described above for thirty times. During the course of repeated experiments, concentrated hydrochloric acid was added so that the pH of the acidic aqueous solution was always maintained between 1 and 2. And, considering the transfer of HCl from an acidic aqueous solution to a basic aqueous solution through an organic solution layer, by conditioningThe pH of the alkaline aqueous solution was fixed to 12.0 by the addition of the whole NaOH. Thirty experimental results are carried out1H NMR testing showed that the chiral selectivity was almost the same for each experiment. Thirty replicates were performed and the organic solution layer recovered after separation of phenylalanine from the acidic aqueous solution layer1H NMR with initial organic solution1H NMR was the same.
Example 6: recovery of phenylalanine from acidic aqueous layer
After thirty replicates of the experiment in example 5, NaOH was added to the acidic aqueous layer, adjusting its pH to 7.0. Then, phenylalanine was precipitated, recovered, washed three times with cold water, and then dried under reduced pressure at 50 ℃. The weight of the dried phenylalanine was 84g, and the total recovery was 94%. Analysis of the dried phenylalanine by High Performance Liquid Chromatography (HPLC) showed 92% of D-phenylalanine and the remainder of L-phenylalanine.
Example 7: experiment for increasing optical purity of phenylalanine
10g (50mmol) of phenylalanine (92% as D-form) obtained in example 6 was dissolved in 100ml of water, and 4.0g (100mmol) of NaOH was slowly added thereto to prepare a phenylalanine salt. The aqueous solution was mixed with CDCl3A mixed solution of/p-tolunitrile (volume ratio: 1) (in which compound 3(3g, 5.4mmol) as an R-optical isomer and Aliquat (3g, 5.4mmol) were dissolved) was mixed and stirred for 5 hours. Warp beam1H NMR analysis of the organic solution layer showed that L-phenylalanine and Compound 3 formed an imine. An organic solution layer was separated, and the organic solution layer was stirred with an aqueous HCl solution for 1 hour, so that L-phenylalanine in the organic solution layer was transferred to the aqueous HCl solution layer. An aqueous HCl layer was prepared under the same conditions as in example 4. The organic solution layer separated from the HCl aqueous solution layer was transferred again to the alkaline aqueous solution layer containing a high concentration of D-phenylalanine, and then the same experiment was performed again. After two identical experiments, the amount of compound 3 as the R-optical isomer in the organic solution layer was reduced to 1/2, and the same experiment was repeated four timesAnd (5) carrying out experiments. HCl was added to a layer of a basic aqueous solution containing a high concentration of D-phenylalanine to adjust its pH to 7.0. The neutral phenylalanine precipitate was filtered, washed three times with cold water, and then dried under reduced pressure at 50 ℃. Dried phenylalanine was measured by HPLC, wherein D-phenylalanine accounted for 99.7%, and the weight was 6.2 g.
Example 8: racemization in aqueous amino acid solutions
DL-phenylalanine (1.0g) and PLP (50mg) were added to D2O (5ml), to which an aqueous NaOH solution was then added while stirring, so that all components were dissolved. At the room temperature, the reaction kettle is used for heating,1h NMR results showed that the alpha-H of phenylalanine was substituted by D. However, the rate of substitution is very low, and after one week, phenylalanine substituted by D only reaches about 30%. Attempts were made to change the amount of PLP, but the D substitution rate decreased rather when the amount of PLP increased, and the substitution rate was still decreased even when PLP was 5% or less of the molar amount of DL-phenylalanine. In the absence of PLP, only a small amount of D substitution occurred after one week. In addition, under the same conditions, when D2When the temperature of the O solution is increased to 70 ℃ or higher, D substitution proceeds at a very fast rate, and at 80 ℃ or higher, D substitution can be completed within 30 minutes. The D substitution indicates racemization of the amino acid, and thus these experimental results indicate the occurrence of racemization.
The same experiment was performed for other amino acids such as serine, methionine, valine, leucine, tryptophan and tyrosine, and the same results were obtained. In the case of valine, racemization is 2-3 times longer than other amino acids.
Example 9: optically selective transfer of other amino acids
Alpha-amino acids (e.g., DL-serine, DL-alanine, DL-valine, DL-leucine and DL-tryptophan), and beta-amino acids (e.g., DL-3-aminobutyric acid, beta-phenylalanine, beta-leucine, beta-homophenylalanine, beta-homoleucine and 3-aminoisobutyric acid) were optically treated in the same manner as in example 5Selective transfer experiments. Chiral selectivity of amino acids transferred from aqueous solution layer to organic solution layer1The calculated value of the peak area of H NMR was determined. The results are shown in Table 1 below.
TABLE 1
As shown in the results of Table 1, one of the facts to be noted is that the process of the present invention also shows high chiral selectivity for valine (. alpha. -amino acid). Valine can be racemized in the aqueous solution layer, and thus the process of the present invention can efficiently perform chiral conversion of an amino acid such as valine. As disclosed in published papers (JACS 2007; che. eur.j 2008), valine cannot undergo chiral transformation when chiral transformation is performed using DMSO solvent. However, since the process of the present invention also achieves a successful chiral conversion for valine, all these results can be seen as a great advance in the art.
And as shown in table 1, the method of the present invention shows high chiral selectivity for β -phenylalanine, β -leucine, β -homophenylalanine and β -homoleucine among β -amino acids. Therefore, the method of the present invention can be effectively applied to optical resolution of these β -amino acids. In the case of beta-amino acids, racemization does not occur in the aqueous solution layer, and therefore, the process of the present invention does not allow chiral conversion of the beta-amino acid, but allows separation of chiral isomers of the beta-amino acid.

Claims (10)

1. A method for preparing an optically pure amino acid, comprising the steps of: an aqueous alkaline solution comprising an amino acid for optical resolution or optical conversion, wherein the amino acid is contained in the aqueous alkaline solution in the form of a lithium salt, a sodium salt, or a potassium salt of the amino acid; an organic solution comprising a chirally selective receptor for chirally selectively reacting with a D-amino acid or an L-amino acid to form an imine, wherein the organic solvent contained in the organic solution is a water-insoluble organic solvent; and an acidic aqueous solution;
the method comprises the following steps:
a first step of mixing the alkaline aqueous solution and the organic solution by stirring and separating an alkaline aqueous solution layer and an organic solution layer;
a second step of mixing the organic solution and the acidic aqueous solution separated in the first step by stirring and separating an acidic aqueous solution layer and an organic solution layer; and
a third step of obtaining a D-amino acid or an L-amino acid from the acidic aqueous solution separated in the second step,
wherein the chiral selective receptor is a compound represented by the following chemical formula 1:
[ chemical formula 1]
Wherein,
r1 is: hydrogen; a C1-C10 alkyl group substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; C4-C10 cycloalkyl substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy; or a C6-C12 aryl group, substituted or unsubstituted with one or more substituents selected from the group consisting of halogen and hydroxy;
r2 is-NHCX 'R3, wherein X' is oxygen or sulfur; r3 is-NR 6R 7; r6 and R7 are each independently hydrogen, C1-C10 alkyl substituted or unsubstituted by halogen, or C6-C12 aryl substituted or unsubstituted by halogen, C1-C5 alkyl and C1-C5 perfluoroalkyl.
2. The method of claim 1, further comprising: repeating the first step and the second step one or more times using the basic aqueous solution separated in the first step and the acidic aqueous solution and the organic solution separated in the second step before performing the third step.
3. The process according to claim 1, wherein the basic aqueous solution further comprises a racemization catalyst for racemizing the amino acid, wherein the racemization catalyst is one or more selected from the group consisting of pyridoxal phosphate and pyridoxal.
4. The process according to claim 3, characterized in that, in order to accelerate the racemization of the amino acid, the basic aqueous solution is heated to 50 to 100 ℃ before the first step is carried out.
5. The method of claim 1, wherein the organic solvent further comprises an organic solvent having a highly polar functional group.
6. The method according to claim 5, wherein the organic solvent is a mixed solvent of dichloromethane and butyronitrile or a mixed solvent of chloroform and tolunitrile.
7. The method of claim 1, wherein the organic solution further comprises a phase transfer catalyst.
8. The method of claim 1, wherein the acidic aqueous solution is an aqueous hydrochloric acid solution.
9. The method of claim 1, wherein the amino acid is an alpha-amino acid.
10. The method of claim 1, wherein the chirally selective receptor is selected from the group consisting of compounds represented by the following chemical formula 3 and chemical formula 4:
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